Homeodomain containing genes encode transcription factors that act during development to control pattern formation, differentiation and proliferation. Based on data from our laboratory and work of others, the quantitative analysis of HOX gene expression promises to be a powerful new tool in the prognostic assessment of patients with acute myelogenous leukemia (AML). To date, characteristic chromosomal alterations have been the gold standard for prognosis in AML. However, 50 percent of AML patients lack cytogenetic changes and another 10-20 percent have alterations considered to be of intermediate importance. Thus, a majority of patients with AML lack sufficient prognostic markers upon which definitive therapeutic decisions can be made. Our studies indicate that the patterns of quantitative HOX gene expression are in near total concordance with favorable and adverse chromosomal features. In addition, these expression patterns extend to the subset of patients with normal cytogenetics and other intermediate changes and are predictive of outcome. We propose to confirm and extend our initial observations on the importance of HOX gene expression in AML. In the R21, we will refine our quantitative assays to include the complete set of HOXA, HOXB and important TALE (PBX, MEIS) family members and validate the analytic performance of these assays. We will also explore the analysis of selected extended HOX and paraHox genes in AML for inclusion in the subsequent R33. The R33 phase will determine the role of quantitative HOX expression as a prognostic marker in AML, the association of HOX expression patterns with specific chromosomal features as well as resistant or relapsed disease, and should permit us to identify the most useful subset of HOX genes based on our analysis of large numbers of patients and disease phenotypes. Lastly, we will determine whether there is a relationship between HOX expression and another new predictor of outcome involving internal tandem duplications or mutations of the FLT3 receptor. Importantly, the HOX genes are more than markers of lineage, or differentiation. Rather, they are integrally involved in the pathogenesis of acute leukemia in both mice and man. Thus, their analysis provides insight into the disease process, and its heterogeneity, while providing new important prognostic information.